Which Estrogen is Best for Postmenopausal Therapy?
By Sarah L. Berga, MD
Until recently, an estrogen was a steroid that fit into the estrogen receptor and initiated post-receptor events within that cell. This simple concept held that there was one estrogen receptor with similar binding affinity in all cell types. New discoveries have shown that this notion is wrong. There are at least two main types of estrogen receptors, ER(symbol) and ER(2nd symbol). There are also proteins known as promoters that assist receptors like ER(symbol) and ER(2nd symbol) in gene activation.1 In the long term, understanding these molecular events may hold the key to unraveling the effects of a given estrogen-like compound, but, in the short term, they make it difficult to predict the effect of different estrogens upon tissues or organs of interest. Not only will some estrogens bind more avidly to one estrogen receptor than the other, but, when both receptors are expressed, they may counteract each other or they may synergize with one another. The distribution of receptor subtypes and promoters within the body's tissues has not been convincingly mapped,2 so it is too early to guess the clinical implications of this burgeoning line of discovery. To complicate matters more, estrogens can have important cellular actions by nongenomic mechanisms, such as altering rates of apoptosis (cell death) or interpolating into neuronal membranes and influencing neuronal excitability. The most daunting complexity of all, however, is the introduction of what are termed selective estrogen receptor modulators (SERMs) for clinical use in the absence of a clear appreciation of estrogen's actions at a cellular level.3 If our information about the cellular actions of estrogens is rudimentary, how can we design or even test the effects of so-called "smart estrogens?"For years, it was hypothesized that women who had breast cancers positive for estogen receptors would experience a greater risk of recurrence if they were given exogenous estrogens after menopause, so they were given anti-estrogens. But, if the breast cancer contains a mutant form of an estrogen receptor, is it still likely that estrogen exposure will promote recurrence?4 Receptor-negative breast cancer may indicate an undifferentiated cell type that would be resistant to regulation by estrogen.
Is estrogen contraindicated in such a patient? Although we long for clear and expeditious answers that aid in streamlining patient care, we must avoid oversimplifying the situation. It is difficult to base clinical decisions on studies that reveal the cellular actions of estrogens, yet epidemiological studies take a long time to perform.
Therefore, quick or definitive answers are unlikely. We need to prepare ourselves for this clinical complexity and guide patients through the maze of false hope and wishful thinking. In this regard, we must recognize that the question constrains the answer. Which estrogen is best? There is only one right answer. It depends. To answer the question more precisely, we must define the dependent variables of interest.
Consider the implications of estrogen use in a woman with a strong family history of dementia vs. the risks and benefits of its use in a woman with a strong family history of breast cancer. Since risk is individual, it stands to reason that the selection of an estrogen for postmenopausal hormone use must be individualized. Will the use of a designer estrogen such as raloxifene protect against dementia? Will raloxifene give better protection against osteoporosis than oral micronized estradiol? Which estrogen is best for diminished libido? Recent studies show that both types of estrogen receptors are present within those parts of the brain that subserve emotionality including libido.5 However, at least some of the mechanisms that guard against dementia appear to be estrogen receptor independent.6
What is the response of the practicing physician to this evolving knowledge? Clearly, we need to develop criteria for how to select a given estrogen type and route, and to base these guidelines on cellular insights, epidemiological trials, and individualized risk assessment. In the meantime, we must help patients reconcile themselves to making decisions in the absence of concrete answers.
We should critically consider the risks and benefits of different estrogen preparations and avoid falling for hype. We also need to evolve better strategies for risk assessment, because we are not all equally vulnerable. The identification of valid surrogate outcome measures would obviate expensive and tedious epidemiological trials.
Finally, we must recognize that the pace of scientific advances and the direct marketing of pharmaceuticals to patients make the input and guidance of the physician more important than ever.
References
1. Pennisi E. Science 1997;277:1439.2. Kuiper GG, Gustafsson JA. FEBS Lett 1997;410:87-90.
3. Hasimoto M, et al. Biochem Biophys Res Commun 1997;240:464-470.
4. Murphy LC, et al. Ann Med 1997;29:221-234.
5. Shugrue PJ, et al. J Comp Neurol 1997;388:507-525.
6. Behl C, et al. Mol Pharmocol 1997;51:535-541.
All of the following statements concerning the study by Schilder et al comparing postoperative patients who were kept NPO to those who were fed early are true except:
a. patients fed early were discharged earlier.
b. patients fed early experienced fewer episodes of vomiting.
c. patients fed early required the same amount of pain medication.
d. patients fed early tolerated solid food earlier.
Early postoperative feeding after major abdominal gynecologic surgery is associated with the following advantage(s):
a. shorter hospital stay.
b. less discomfort.
c. improved nutrition.
d. enhanced patient satisfaction.
e. All of the above
In the study by Dyson et al, daily home uterine activity monitoring in patients at risk for preterm labor led to which of the following?
a. An increase in births more than 35 weeks gestation
b. An increase in births more than 32 weeks gestation
c. A decrease in prophylactic tocolytic treatment
d. An increase in birth weights greater than 1500 g
e. An increase in unscheduled visits to the obstetrician
The most common biopsy finding associated with the cytologic diagnosis of "atypical glandular cells of uncertain significance" is:
a. endometrial cancer.
b. cystic endometrial hyperplasia.
c. atypical endometrial hyperplasia.
d. squamous intraepithelial lesion.
e. invasive squamous cell carcinoma.
In the study of regional analgesia in labor by Nageotte at al, low-dose combined spinal-epidural analgesia resulted in:
a. fewer cesarean sections.
b. higher five-minute Apgar scores.
c. fewer instrumental vaginal deliveries.
d. higher patient satisfaction ratings.
The following statements are true of PMS except:
a. PMS is due to a deficiency of progesterone.
b. PMS patients have normal sex hormone levels.
c. eliminating menstrual cycle hormonal changes improves PMS symptoms in most patients.
d. not every PMS patient responds favorably to GnRH agonist treatment.
Based on the study of Fernandez et al, which of the following increases the likelihood of success with external cephalic version for a breech presentation at term?
a. Terbutaline
b. Engagement of the breech
c. Maternal obesity
d. Decreased amniotic fluid
e. Anterior placenta
Which of the following statements is false?
a. The design of selective estrogen receptor modulators is complicated by the existence of more than one type of estrogen receptor.
b. Predicting the risks and benefits of long-term hormone exposures is complicated by the lack of surrogate end points that can be readily assessed.
c. When pharmaceutical companies advertise directly to consumers, they abrogate the physician's role in clinical management.
d. The nongenomic actions of estrogens are strictly hypothetical and do not influence clinical decisions.
e. Patients find it difficult to base medical decisions upon epidemiological information and need physician guidance.
Correction
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